PROJECT SUMMARY Osteoarthritis, or degeneration of cartilage, is one of the most prevalent joint diseases and remains the most common cause of work-related disabilities in this country. Current osteoarthritis treatment options often fail due to lack of integration between the cartilage graft and the host tissues, including both the surrounding cartilage and underlying bone. Therefore, there exists an unmet clinical need for integrative solutions for cartilage repair. The objective of the proposal is to determine the efficacy of an integrative nanofiber cup system in promoting graft-cartilage and graft-bone integration. It is hypothesized that native cartilage integration will be facilitated by controlling chondrocyte migration to the graft-cartilage junction, and osteointegration will be enhanced by optimizing calcium phosphate (CaP) nanoparticle bioactivity, concentration and spatial distribution. To test this hypothesis, the nanofiber cup system will be evaluated both in vitro (Aims 1 and 2) and in vivo (Aim 3) with a hydrogel-based cartilage graft that exhibits mechanical properties within the range of articular cartilage. An osteochondral explant model will be used to test both graft-cartilage and graft-bone integration in vitro, while a clinically relevant rabbit osteoarthritis model will be used to test host tissue integration in vivo. In addition to evaluating cell and tissue phenotypes via immunohistochemistry and biochemical assays, other functional outcomes such as integration strength and quantitative compositional mapping across tissue boundaries will also be used to determine efficacy in vitro and in vivo. In addition to targeting a clinically significant problem, the proposed approach represents a new paradigm in cartilage repair. The nanofiber integration system is novel because of its: 1) unique nanofiber-based cup design, 2) ability to promote simultaneous graft-cartilage and graft-bone integration, and 3) compatibility with a variety of cartilage grafts. This innovative approach for integrated cartilage repair will enable the restoration of cartilage integrity and long-term function. Moreover, it will help to prevent further joint degeneration and thereby reduce the need for aggressive and often suboptimal interventions (e.g. total joint replacements and related revision surgeries). Successful completion of the planned studies will lead to the development of a new generation of nanotechnology-based fixation devices for the treatment of soft tissue injuries.